US8247374B2 - Methods and compositions for the repair and/or regeneration of damaged myocardium using cytokines and variants thereof - Google Patents

Methods and compositions for the repair and/or regeneration of damaged myocardium using cytokines and variants thereof Download PDF

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US8247374B2
US8247374B2 US12/267,849 US26784908A US8247374B2 US 8247374 B2 US8247374 B2 US 8247374B2 US 26784908 A US26784908 A US 26784908A US 8247374 B2 US8247374 B2 US 8247374B2
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heart
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Piero Anversa
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New York Medical College
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1808—Epidermal growth factor [EGF] urogastrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates generally to the field of cardiology, and more particularly relates to methods and cellular compositions for treatment of a patient suffering from a cardiovascular disease, including, but not limited to, atherosclerosis, ischemia, hypertension, restenosis, angina pectoris, rheumatic heart disease, congenital cardiovascular defects and arterial inflammation and other disease of the arteries, arterioles and capillaries.
  • a cardiovascular disease including, but not limited to, atherosclerosis, ischemia, hypertension, restenosis, angina pectoris, rheumatic heart disease, congenital cardiovascular defects and arterial inflammation and other disease of the arteries, arterioles and capillaries.
  • the present invention contemplates treatments, therapeutics and methodologies that can be used in place of, or in conjunction with, traditional, invasive therapeutic treatments such as cardiac or vascular bypass surgery.
  • Cardiovascular disease is a major health risk throughout the industrialized world.
  • Atherosclerosis the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principal cause of death in the United States.
  • Atherosclerosis is a complex disease involving many cell types and molecular factors (for a detailed review, see Ross, 1993, Nature 362: 801-809).
  • Ischemia is a condition characterized by a lack of oxygen supply in tissues of organs due to inadequate perfusion. Such inadequate perfusion can have number of natural causes, including atherosclerotic or restenotic lesions, anemia, or stroke, to name a few. Many medical interventions, such as the interruption of the flow of blood during bypass surgery, for example, also lead to ischemia. In addition to sometimes being caused by diseased cardiovascular tissue, ischemia may sometimes affect cardiovascular tissue, such as in ischemic heart disease. Ischemia may occur in any organ, however, that is suffering a lack of oxygen supply.
  • MI myocardial infarction
  • a heart attack is one of the most well-known types of cardiovascular disease.
  • MI is caused by a sudden and sustained lack of blood flow to an area of the heart, commonly caused by narrowing of a coronary artery. Without adequate blood supply, the tissue becomes ischemic, leading to the death of myocytes and vascular structures.
  • This area of necrotic tissue is referred to as the infarct site, and will eventually become scar tissue. Survival is dependent on the size of this infarct site, with the probability of recovery decreasing with increasing infarct size. For example, in humans, an infarct of 46% or more of the left ventricle triggers irreversible cardiogenic shock and death (99).
  • Stem cells have the ability to divide indefinitely, and to specialize into specific types of cells.
  • Totipotent stem cells which exist after an egg is fertilized and begins dividing, have total potential, and are able to become any type of cell. Once the cells have reached the blastula stage, the potential of the cells has lessened, with the cells still able to develop into any cell within the body, however they are unable to develop into the support tissues needed for development of an embryo.
  • the cells are considered pluripotent, as they may still develop into many types of cells. During development, these cells become more specialized, committing to give rise to cells with a specific function.
  • These cells, considered multipotent are found in human adults and referred to as adult stem cells. It is well known that stem cells are located in the bone marrow, and that there is a small amount of peripheral blood stem cells that circulate throughout the blood stream (National Institutes of Health, 2000).
  • stem cells Due to the regenerative properties of stem cells, they have been considered an untapped resource for potential engineering of tissues and organs. It would be an advance to provide uses of stem cells with respect to addressing cardiac conditions.
  • PCT/US00/08353 (WO 00/57922) and PCT/US99/17326 (WO 00/06701) involving intramyocardial injection of autologous bone marrow and mesenchymal stem cells which fails to teach or suggest administering, implanting, depositing or the use of hematopoietic or cardiac stem cells as in the present invention, especially as the hematopoietic and cardiac stem cells as in the present invention are advantageously isolated and/or purified adult hematopoietic or cardiac stem cells.
  • stem cells in medicine are for the treatment of cancer.
  • bone marrow is transplanted into a patient whose own marrow has been destroyed by radiation, allowing the stem cells in the transplanted bone marrow to produce new, healthy, white blood cells.
  • stem cells are transplanted into their normal environment, where they continue to function as normal.
  • any particular stem cell line was only capable of producing three or four types of cells, and as such, they were only utilized in treatments where the stem cell was required to become one of the types of cells for which their ability was already proven.
  • researchers are beginning to explore other options for treatments of myriad disorders, where the role of the stem cell is not well defined.
  • the method further comprises administering a second cytokine, wherein the second cytokine induces proliferation of adult cardiac stem cells.
  • the second cytokine is insulin-like growth factor-1.
  • the invention also provides methods and/or compositions for forming coronary vasculature in an infracted portion of the ventricular wall comprising administering to the subject an effective amount of at least one variant of hepatocyte growth factor to form a chemotactic gradient in the subject's heart sufficient to cause adult cardiac stem cells resident in the heart to replicate and migrate to the area of the infarction, wherein vasculogenesis forms coronary vasculature in the infarcted portion of the ventricular wall following the migration of adult cardiac stem cells to the infarcted portion.
  • the invention also encompasses growth media that can be used in the culture and expansion of adult cardiac stem cells, in particular human cardiac stem cells. Also provided is growth media that can be used to activate cardiac stem cells, in particular human cardiac stem cells. Cardiac stem cells grown in said media can be administered to regenerate myocardium or vasculature. Activated stem cells grown in the media can also be administered to regenerate myocardium or vasculature, wherein vasculature includes large arteries and veins, such as in a biological bypass.
  • the present invention also provides a method of adult cardiac stem cells.
  • the method comprises incubating isolated adult cardiac stem cells in a solution comprising at least one cytokine, wherein the at least one cytokine is a variant of hepatocyte growth factor.
  • Suitable variants of hepatocyte growth factor include NK1, 1K1, 1K2, HP11, and HP21.
  • said variant of hepatocyte growth factor is NK1.
  • the solution for activating adult cardiac stem cells may further comprise a second cytokine, wherein the second cytokine induces proliferation of adult cardiac stem cells.
  • said second cytokine is insulin-like growth factor-1.
  • the invention also provides methods and/or compositions for forming coronary vessels or arteries in a patient in need thereof comprising administering activated cardiac stem cells to the location in which a vessel or artery is desired.
  • the cardiac stem cells may be isolated and activated by exposing the cardiac stem cells to one or more variants of hepatocyte growth factor including HP11, NK1, and 1K1. These methods can potentially generate a biological bypass of an occluded or obstructed artery to allow for reperfusion of the ischemic tissue. Such methods can be used in place of, or in conjunction with, traditional methods of cardiac bypass surgery.
  • the invention provides methods and/or compositions for repairing and/or regenerating recently damaged myocardium and/or myocardial cells comprising the administration of somatic stem cells, e.g., adult stem cells or cardiac stem cells or hematopoietic stem cells or a combination thereof, such as adult cardiac or adult hematopoietic stem cells or a combination thereof or a combination of cardiac stem cells and a stem cell of another type, such as a combination of adult cardiac stem cells and adult stem cells of another type.
  • the invention provides media for use in the culturing and/or expansion of stem cells in vitro, prior to the administration of the stem cells.
  • said media includes one or more variants of hepatocyte growth factor to activate the stem cells prior to administration.
  • the present invention also encompasses a method for restoring structural and functional integrity to damaged myocardium in a subject in need thereof comprising extracting cardiac stem cells from the subject; culturing and expanding said cardiac stem cells; activating the extracted and expanded cardiac stem cells by exposing the cardiac stem cells to at least one variant of hepatocyte growth factor; and administering an effective dose of said activated cardiac stem cells to an area of damaged myocardium in the subject, wherein the activated cardiac stem cells restore structural and functional integrity to the damaged myocardium following their administration.
  • extracting cardiac stem cells from the subject comprises harvesting myocardial tissue from the subject and isolating the cardiac stem cells from said myocardial tissue.
  • the activated cardiac stem cells are administered intracoronarily.
  • the activated cardiac stem cells differentiate into myocytes, smooth muscle cells, and endothelial cells following their administration and form myocardial tissue and coronary vessels.
  • the invention still further relates to a method and/or compositions for repairing and/or regenerating recently damaged myocardium comprising the administration of somatic stem cells, e.g., adult stem cells or cardiac stem cells or hematopoietic stem cells or a combination thereof, such as adult cardiac or adult hematopoietic stem cells or a combination thereof or a combination of cardiac stem cells and a stem cell of another type, such as a combination of adult cardiac stem cells and adult stem cells of another type and a cytokine or variant thereof.
  • somatic stem cells e.g., adult stem cells or cardiac stem cells or hematopoietic stem cells or a combination thereof, such as adult cardiac or adult hematopoietic stem cells or a combination thereof or a combination of cardiac stem cells and a stem cell of another type, such as a combination of adult cardiac stem cells and adult stem cells of another type and a cytokine or variant thereof.
  • ” can include sequential implanting, depositing administering or causing of implanting or depositing or administering of the stem cells and the cytokine or the co-implanting co-depositing or co-administering or causing of co-implanting or co-depositing or co-administering or the simultaneous implanting, depositing administering or causing of implanting or depositing or administering of the stem cells and the cytokine), in circulatory tissue or muscle tissue or circulatory muscle tissue, e.g., cardiac tissue, such as the heart or blood vessels—e.g., veins, arteries, that go to or come from the heart such as veins and arteries directly connected or attached or flowing into the heart, for instance the aorta.
  • This implanting, depositing, or administering or causing of implanting, depositing or administering can be in conjunction with grafts.
  • Such implanting, depositing or administering or causing of implanting, depositing or administering is advantageously employed in the treatment or therapy or prevention of cardiac conditions, such as to treat areas of weakness or scarring in the heart or prevent the occurrence or further occurrence of such areas or to treat conditions which cause or irritate such areas, for instance myocardial infarction or ischemia or other e.g., genetic, conditions that impart weakness or scarring to the heart (see also cardiac conditions mentioned supra).
  • the invention additionally provides the use of such stem cells alone or in combination with said cytokine(s) or variants thereof, in the formulation of medicaments for such treatment, therapy or prevention.
  • kits comprising the stem cells and optionally the cytokine(s) or variants thereof for formulations for use in such treatment, therapy or prevention.
  • the stem cells and the cytokine(s) can be in separate containers in a package or in one container in a package; and, the kit can optionally include a device for administration (e.g., syringe, catheter, etc.) and/or instructions for administration and/or admixture.
  • the invention also provides compositions comprising such stem cells and optionally the cytokine(s) or cytokine variants and kits for preparing such compositions as well as methods of making the aforementioned compositions.
  • the invention also provides a means of generating and/or regenerating myocardium ex vivo, wherein somatic stem cells and heart tissue are cultured in vitro, optionally in the presence of a cytokine or cytokine variant.
  • the somatic stem cells differentiate into myocytes, smooth muscle cells and endothelial cells, and proliferate in vitro, forming myocardial tissue and/or cells.
  • These tissues and cells may assemble into cardiac structures including arteries, arterioles, capillaries, and myocardium.
  • the tissue and/or cells formed in vitro may then be implanted into a patient, e.g. via a graft, to restore structural and functional integrity.
  • FIG. 1 Migration of implanted human cardiac stem cells activated with NK1 and IGF-1 to infarct site in a mouse model of myocardial infarction.
  • EGFP POS -c-kit POS -cardiac stem cells CSCs
  • the three different panels show the migration of the EGFP POS stem cells over time (A, B, and C represent time points: 0, 1 hour and 2 hours, respectively).
  • Red label rhodamine-labeled microspheres co-injected with the human CSCs to mark the sites of injection.
  • FIG. 2 Myocardial regeneration induced by NK1 and IGF-1 after infarction.
  • Two examples (panels A and B) demonstrating the replacement of a mid-portion of the infarct by a band of regenerated myocytes ten days after coronary artery occlusion and the intramyocardial injection of IGF-1 and NK1.
  • the newly formed myocytes can be identified by the red fluorescence labeling of ⁇ -sarcomeric actin. Blue fluorescence corresponds to nuclei stained by DAPI.
  • stem cell refers to either autologous or allogenic stem cells, which may be obtained from the bone marrow, peripheral blood, or other source (e.g. heart).
  • autologous refers to something that is derived or transferred from the same individual's body (i.e., autologous blood donation; an autologous bone marrow transplant).
  • allogenic refers to something that is genetically different although belonging to or obtained from the same species (e.g., allogeneic tissue grafts).
  • “recently damaged myocardium” refers to myocardium which has been damaged within one week of treatment being started. In a preferred embodiment, the myocardium has been damaged within three days of the start of treatment. In a further preferred embodiment, the myocardium has been damaged within 12 hours of the start of treatment. It is advantageous to employ stem cells alone or in combination with cytokines or variants thereof as herein disclosed to a recently damaged myocardium.
  • damaged myocardium refers to myocardial cells which have been exposed to ischemic conditions. These ischemic conditions may be caused by a myocardial infarction, or other cardiovascular disease or related complaint. The lack of oxygen causes the death of the cells in the surrounding area, leaving an infarct, which will eventually scar.
  • assemble refers to the assembly of differentiated somatic stem cells into functional structures, e.g. myocardium and/or myocardial cells, coronary arteries, arterioles, and capillaries etc. This assembly provides functionality to the differentiated myocardium and/or myocardial cells, coronary arteries, arterioles and capillaries.
  • the variant can have “conservative” changes, wherein a substituted amino acid has similar structural or chemical properties, e.g., replacement of leucine with isoleucine.
  • a variant can have “nonconservative” changes, e.g., replacement of a glycine with a tryptophan.
  • Analogous minor variations can also include amino acid deletion or insertion, or both. Guidance in determining which amino acid residues can be substituted, inserted, or deleted without eliminating biological activity can be found using computer programs well known in the art, for example, DNASTAR software.
  • patient or “subject” may encompass any vertebrate including but not limited to humans, mammals, reptiles, amphibians and fish.
  • the patient or subject is a mammal such as a human, or a mammal such as a domesticated mammal, e.g., dog, cat, horse, and the like, or production mammal, e.g., cow, sheep, pig, and the like.
  • somatic stem cells into the myocardium surrounding an infarct following a myocardial infarction, migrate into the damaged area, where they differentiate into myocytes, endothelial cells and smooth muscle cells and then proliferate and form structures including myocardium, coronary arteries, arterioles, and capillaries, restoring the structural and functional integrity of the infarct.
  • CSCs resident cardiac stem cells
  • atria 82
  • rat 83, 84
  • CSCs express surface antigens commonly found in hematopoietic and skeletal muscle stem cells (85, 86).
  • CSCs are clonogenic, self-renewing and multipotent giving rise to all cardiac lineages (84).
  • the injured heart has the potential to repair itself.
  • this possibility had been limited by our lack of understanding of CSC colonization, proliferation and differentiation in new organized, functioning myocardium (61, 87). Identical obstacles apply to any other source of stem cells in the organism (88).
  • the invention provides methods and/or pharmaceutical compositions comprising a therapeutically effective amount of one or more cytokines or cytokine variants for causing the migration and/or proliferation of cardiac stem cells or cardiac primative cells into circulatory tissue or muscle tissue or circulatory muscle tissue, e.g., cardiac tissue, such as the heart or blood vessels—e.g., veins, arteries, that go to or come from the heart such as veins and arteries directly connected or attached or flowing into the heart, for instance the aorta.
  • cardiac tissue such as the heart or blood vessels—e.g., veins, arteries, that go to or come from the heart such as veins and arteries directly connected or attached or flowing into the heart, for instance the aorta.
  • U.S. Patent Application Publication No. 2006/0083712 discloses methods of mobilizing somatic stem cells into the blood stream by administration of cytokines.
  • the methods disclosed in U.S. Patent Application Publication No. 2006/0083712 which is herein incorporated by reference in its entirety, involve the mobilization of stem cells from the bone marrow into the blood stream where they subsequently home to areas of damage within the heart.
  • the cytokines used in these methods are distinct from those disclosed in the instant invention.
  • Variants of HGF including substitutions of specific amino acids and splice variants of the full length native transcript (e.g. NK1), exhibit c-MET receptor agonist activity and can mobilize CSCs to sites of tissue damage. Moreover, some of these variants exhibit longer protein half lives and enhanced biological activity compared to full-length HGF.
  • NK1 full length native transcript
  • IGF-1 Insulin-like growth factor-1
  • IGF-1 is mitogenic, anti-apoptotic and is necessary for neural stem cell multiplication and differentiation (96, 97, 98).
  • IGF-1 impacts CSCs by increasing their number and protecting their viability.
  • IGF-1 overexpression is characterized by myocyte proliferation in the adult mouse heart (65) and this cell growth may depend on CSC activation, differentiation and survival.
  • Hepatocyte growth factor also known as scatter factor (SF) plays a role in the development of epithelial organs, such as the liver, through its activation of the c-MET receptor tyrosine kinase (Schmidt, C. et al, 1995; Bottaro, D. P. et al., 1991). It has also been shown to cause migration of myogenic precursor cells (Bladt et al., 1995) and motor neurons (Caton et al., 2000; Ebens et al., 1996). In addition, HGF has been shown to be effective in mobilizing resident cardiac stem cells to areas of myocardial damage (see U.S. Patent Application Publication No. 2003/0054973, which is herein incorporated by reference in its entirety).
  • HGF The structure of HGF can be divided into six domains: an N-terminal domain (N), four copies of the kringle domain (K), and a catalytically inactive serine proteinase domain (Donate et al., 1994).
  • the primary HGF transcript can be alternatively spliced to produce two distinct products: NK1 comprised of the N-terminal domain and the first kringle domain, and NK2 containing the N-terminal domain and the first two kringle domains (Cioce et al., 1996; Miyazawa et al., 1991).
  • NK1 has been reported to be a partial agonist of the c-MET receptor (Cioce et al., 1996; Jakubczak et al., 1998).
  • HGF The natural growth and motility factor HGF acts locally in the tissues in a paracrine manner and, once secreted by producer cells, is sequestered by the extracellular matrix. Heparan sulphate proteoglycans bind HGF with nanomolar affinity. The high pI and the strong affinity of HGF for matrix components are reflected in the behaviour of the recombinant protein in solution. In buffers of low or physiological ionic strength, HGF is polydisperse and aggregated as shown by analytical ultracentrifugation experiments and cannot be eluted from gel filtration columns. However, the protein behaves as a monomer and is stable in buffers containing at least 0.5 M NaCl.
  • the NK1 fragment is considerably more stable in the test tube.
  • the NK1 protein retains the high-affinity binding site for heparan sulphate proteoglycans in the N-terminal domain, but lacks the second, third and fourth kringle domains and the serine proteinase homology domain, resulting in NK1 behaving as stable monomer in solution in buffers of physiological ionic strength.
  • engineered derivatives of NK1 such as 1K1 which carries two reverse charge mutations in the kringle 1 domain (K132E and R134E).
  • variants of HGF with reduced affinity for heparan sulphate proteoglycans were shown to be more stable in the test tube and have a longer half life in vivo (Hartmann et al., 1998).
  • NK1 and HGF with altered heparin binding properties were reported to have variable receptor agonist activity (see U.S. Pat. No. 7,179,786, which is herein incorporated by reference in its entirety).
  • NK1 and 1K1 provided enhanced protection compared to HGF against ⁇ -amanitin-induced liver failure in mice.
  • 1K1 and a second mutant of NK1 termed 1K2 (K170E, R181E) showed enhanced biological activity (e.g. stimulation of DNA synthesis, colony scatter activity) compared to wild-type NK1 or full-length HGF (Lietha et al., 2001).
  • the present invention provides a method for restoring functional and structural integrity to damaged myocardium in a subject in need thereof by administering an effective amount of at least one variant of hepatocyte growth factor.
  • the method comprises administering to the subject an effective amount of at least one variant of hepatocyte growth factor to form a chemotactic gradient in the subject's heart sufficient to cause adult cardiac stem cells resident in the heart to replicate and migrate to the area of the damaged myocardium, wherein the functional and structural integrity of the damaged myocardium is restored following the migration of adult cardiac stem cells to the area of damaged myocardium.
  • the at least one variant of hepatocyte growth factor is administered at varying concentrations of about 0.1 to about 400 ng/ml at different places of administration. In another embodiment, the at least one variant of hepatocyte growth factor is administered at varying concentrations of about 50 to about 200 ng/ml at different places of administration. In still another embodiment, the varying concentrations of the at least one variant of hepatocyte growth factor increase progressively in a direction towards the damaged myocardium.
  • the at least one variant of hepatocyte growth factor is administered at a concentration of about 10 to about 500 ng/ml, about 20 to about 400 ng/ml, about 30 to about 300 ng/ml, about 50 to about 200 ng/ml, or about 80 to about 150 ng/ml.
  • the cytokines are advantageously administered by injection, specifically an intramyocardial injection. As one skilled in the art would appreciate, this is the preferred method of delivery for cytokines as the heart is a functioning muscle. Injection of the cytokines into the heart ensures that they will not be lost due to the contracting movements of the heart.
  • the cytokines are administered by injection transendocardially or trans-epicardially.
  • This preferred embodiment allows the cytokines to penetrate the protective surrounding membrane, necessitated by the embodiment in which the cytokines are injected intramyocardially.
  • a preferred embodiment of the invention includes use of a catheter-based approach to deliver the trans-endocardial injection. The use of a catheter precludes more invasive methods of delivery wherein the opening of the chest cavity would be necessitated.
  • cytokines are delivered to the subject's heart by a single administration.
  • cytokines are delivered to the subject's heart by multiple administrations of the same dosage of cytokines.
  • the invention includes administration of multiple doses of the cytokines to the heart, such that a chemotactic gradient is formed.
  • a method for restoring functional and structural integrity to damaged myocardium in a subject in need thereof comprises administering to the subject an effective amount of at least one variant of hepatocyte growth factor to form a chemotactic gradient in the subject's heart sufficient to cause adult cardiac stem cells resident in the heart to replicate and migrate to the area of the damaged myocardium, wherein said gradient is formed by multiple injections of said at least one variant of hepatocyte growth factor from storage areas of said resident adult cardiac stem cells to a border zone of the damaged myocardium, and wherein the functional and structural integrity of the damaged myocardium is restored following the migration of adult cardiac stem cells to the area of damaged myocardium.
  • Storage areas of resident adult cardiac stem cells may include one or more of the subject's myocardial apex, left atrium, and right atrium.
  • the multiple injections comprise variable concentrations of said variant of hepatocyte growth factor.
  • at least two of the injections are done at opposite sides of the border zone.
  • the present invention also provides methods and/or pharmaceutical compositions comprising a therapeutically effective amount of somatic stem cells alone or in combination with one or more cytokines described above.
  • the invention involves the use of somatic stem cells. These are present in animals in small amounts, but methods of collecting stem cells are known to those skilled in the art.
  • the stem cells are selected to be lineage negative.
  • lineage negative is known to one skilled in the art as meaning the cell does not express antigens characteristic of specific cell lineages.
  • the lineage negative stem cells are selected to be c-kit positive.
  • c-kit is known to one skilled in the art as being a receptor which is known to be present on the surface of stem cells, and which is routinely utilized in the process of identifying and separating stem cells from other surrounding cells.
  • the invention further involves a therapeutically effective dose or amount of stem cells applied to the heart.
  • An effective dose is an amount sufficient to effect a beneficial or desired clinical result.
  • Said dose could be administered in one or more administrations.
  • Effective doses could be determined by the skilled artisan as described in U.S. Patent Application Publication No. 2006/0239983, which is herein incorporated by reference in its entirety.
  • U.S. Patent Application Publication No. 2006/0239983 discloses methods of activating and using isolated adult stem cells for regenerating damaged myocardium and coronary vasculature, and describes examples in which 2 ⁇ 10 4 -1 ⁇ 10 5 stem cells were administered in a mouse model of myocardial infarction.
  • the stem cells are advantageously bone marrow or are cardiac stem cells; and even more advantageously, the stem cells are adult bone marrow (hematopoietic stem cells) or adult cardiac stem cells or a combination thereof or a combination of cardiac stem cells such as adult cardiac stem cells and another type of stem cell such as another type of adult stem cells.
  • the stem cells are adult bone marrow (hematopoietic stem cells) or adult cardiac stem cells or a combination thereof or a combination of cardiac stem cells such as adult cardiac stem cells and another type of stem cell such as another type of adult stem cells.
  • the stem cells are delivered to the heart, specifically to the border area of the infarct.
  • the infarcted area is visible grossly, allowing this specific placement of stem cells to be possible.
  • the stem cells are advantageously administered by injection, specifically an intramyocardial injection. Injection of the stem cells into the heart ensures that they will not be lost due to the contracting movements of the heart. In another embodiment, the cardiac stem cells are administered intracoronarily.
  • the stem cells are administered by injection transendocardially or trans-epicardially.
  • This preferred embodiment allows the stem cells to penetrate the protective surrounding membrane, necessitated by the embodiment in which the cells are injected intramyocardially.
  • a preferred embodiment of the invention includes use of a catheter-based approach to deliver the trans-endocardial injection.
  • the use of a catheter precludes more invasive methods of delivery wherein the opening of the chest cavity would be necessitated.
  • optimum time of recovery would be allowed by the more minimally invasive procedure, which as outlined here, includes a catheter approach.
  • a catheter approach includes the use of such techniques as the NOGA catheter or similar systems.
  • the NOGA catheter system facilitates guided administration by providing electromechanic mapping of the area of interest, as well as a retractable needle that can be used to deliver targeted injections or to bathe a targeted area with a therapeutic. Any of the embodiments of the present invention can be administered through the use of such a system to deliver injections or provide a therapeutic.
  • One of skill in the art will recognize alternate systems that also provide the ability to provide targeted treatment through the integration of imaging and a catheter delivery system that can be used with the present invention.
  • Information regarding the use of NOGA and similar systems can be found in, for example, Sherman, 2003; Patel, 2005; and Perrin, 2003; the text of each of which are incorporated herein in their entirety.
  • FIG. 1 Another embodiment of the invention requires the stem cells to migrate into the infarcted region and differentiate into myocytes, smooth muscle cells, and endothelial cells.
  • Another embodiment of the invention includes the proliferation of the differentiated cells and the formation of the cells into cardiac structures including coronary arteries, arterioles, capillaries, and myocardium (e.g. myocardial tissue and myocardial vessels). It is known in the art that these types of cells and structures must be present to restore both structural and functional integrity. Other approaches to repairing infarcted or ischemic tissue have involved the implantation of these differentiated cells directly into the heart, or as cultured grafts, such as in U.S. Pat. Nos. 6,110,459, and 6,099,832.
  • a still further embodiment of the invention includes the stimulation, migration, proliferation and/or differentiation of the resident cardiac stem cells.
  • the invention also encompasses methods and compositions for the treatment of vasculature disorders or disease, including the occlusion or blockage of a coronary artery or vessel. These methods and compositions can be used for such therapeutic treatment as an alternative to, or in combination with, cardiac bypass surgery.
  • the present invention provides for the isolation, expansion, activation, and implantation or delivery of activated stem cells, preferably activated cardiac stem cells, to an area of the vasculature in need thereof.
  • Such delivery or implantation can be accomplished by any of the methods described herein or which are known to those of skill in the art, including, but not limited to, the use of a NOGA catheter system such that visualization of the area to be treated is possible, and the therapeutic is delivered via a retractable needle associated with such catheter system.
  • One of skill in the art will recognize other useful methods of delivery or implantation which can be utilized with the present invention, including those described in Dawn, 2005, the contents of which are incorporated herein in their entirety.
  • cardiac tissue is harvested from a patient in need of therapeutic treatment for one of the cardiac or vasculature conditions described herein.
  • the present invention provides for the isolation of stem cells, preferably cardiac stem cells, more preferably c-kit POS cardiac stem cells, which are cultured and expanded in vitro.
  • the present invention provides media for use in the culture and expansion of stem cells, preferably cardiac stem cells, more preferably human c-kit POS cardiac stem cells.
  • Such media can comprise DMEM/F12, patient serum, insulin, transferrin and sodium selenite.
  • the media can further comprise one or more of human recombinant bFGF, human recombinant EGF, uridine and inosine.
  • components of the medium can be present in approximate ranges as follows:
  • substitutions of the components of the media may be made as known by those of skill in the art.
  • insulin can be substituted with insulin-like growth factor-1.
  • Uridine and inosine can be substituted with mixtures of other nucleotides, including adenosine, guanosine, xanthine, thymidine, and cytidine.
  • the above media can be utilized during the culturing and expansion of stem cells that are to be administered in order to regenerate or create new myocardium in a damaged or infacted area of the heart.
  • the cultured and expanded stem cells preferably cardiac stem cells, more preferably human c-kit POS cardiac stem cells, are activated prior to their implantation or delivery.
  • the present invention provides a method of activating adult cardiac stem cells comprising incubating isolated adult cardiac stem cells in a solution comprising at least one cytokine.
  • Cytokines or growth factors suitable for use in the method of the invention include any of those described herein, including, but not limited to: Activin A, Angiotensin II, Bone Morphogenic Protein 2, Bone Morphogenic Protein 4, Bone Morphogenic Protein 6, Cardiotrophin-1, Fibroblast Growth Factor 1, Fibroblast Growth Factor 4, Flt3 Ligand, Glial-Derived Neurotrophic Factor, Heparin, Hepatocyte Growth Factor, Insulin-like Growth Factor-1, Insulin-like Growth Factor-II, Insulin-Like Growth Factor Binding Protein-3, Insulin-Like Growth Factor Binding Protein-5, Interleukin-3, Interleukin-6, Interleukin-8, Leukemia Inhibitory Factor, Midkine, Platelet-Derived Growth Factor AA, Platelet-Derived Growth Factor BB, Progesterone, Putrescine, Stem Cell Factor, Stromal-Derived Factor-1, Thrombopoi
  • the stem cells are contacted with hepatocyte growth factor (HGF) and/or insulin-like growth factor-1 (IGF-1).
  • HGF hepatocyte growth factor
  • IGF-1 insulin-like growth factor-1
  • the stem cells are activated by incubating the stem cells with a solution comprising a variant of HGF as described herein.
  • the variant of HGF may include NK1, 1K1, 1K2, HP11, or HP21.
  • the variant of HGF is NK1.
  • the variant of HGF is 1K1.
  • the HGF or variant of HGF is present in an amount of about 0.1 to about 400 ng/ml.
  • the HGF or variant thereof is present in an amount of about 25, about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375 or about 400 ng/ml.
  • the activation solution further comprises a second cytokine, wherein the second cytokine induces proliferation of adult cardiac stem cells.
  • the second cytokine is IGF-1.
  • the IGF-1 may be present in an amount of about 0.1 to about 500 ng/ml.
  • the IGF-1 is present in an amount of about 25, about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, or about 500 ng/ml.
  • the one or more cytokines or growth factors can be present in the media provided herein, such that in one embodiment, the media comprises one or more growth factors or cytokines, DMEM/F12, patient serum, insulin, transferrin and sodium selenite and optionally one or more of human recombinant bFGF, human recombinant EGF, uridine and inosine. It is contemplated that the components of the media can be present in the amounts described herein, and one of skill in the art will be able to determine a sufficient amount of the one or more growth factors or cytokines in order to obtain activation of any stem cells contacted therewith.
  • activated stem cells preferably activated cardiac stem cells, more preferable activated human c-kit POS cardiac stem cells are delivered to, or implanted in, an area of the vasculature in need of therapy or repair.
  • the activated stem cells are delivered to, or implanted in, the site of an occluded or blocked cardiac vessel or artery.
  • cardiac stem cells that are c-kit POS are delivered to, or implanted in, the area in need of therapy or repair.
  • the activated stem cells form into an artery or vessel at the site at which the stem cells were delivered or implanted.
  • the formed artery or vessel has a diameter ranging from about 6 to about 250 ⁇ m, wherein the artery or vessel is formed within one month after administration of the activated cardiac stem cells. In yet a further embodiment, the formed artery or vessel has a diameter of over 100 ⁇ m. In yet a further embodiment, the formed artery or vessel has a diameter of at least 125, at least 150, at least 175, at least 200, at least 225, at least 250 or at least 275 ⁇ m. In yet another embodiment of the present invention, the formed artery or vessel provides a “biological bypass” around the area in need of therapy or repair, including around an occlusion or blockage such that blood flow, blood pressure, and circulation are restored or improved. In yet a still further embodiment of the present invention, the administration of activated stem cells can be done in conjunction with other therapeutic means, including but not limited to the administration of other therapeutics, including one or more growth factors or cytokines.
  • the present invention provides a method for restoring structural and functional integrity to damaged myocardium in a subject in need thereof comprising extracting cardiac stem cells from the subject; culturing and expanding said cardiac stem cells; activating the extracted and expanded cardiac stem cells by exposing the cardiac stem cells to at least one cytokine; and administering an effective dose of said activated cardiac stem cells to an area of damaged myocardium in the subject, wherein the activated cardiac stem cells restore structural and functional integrity to the damaged myocardium following their administration.
  • the at least one cytokine is a variant of hepatocyte growth factor.
  • One embodiment of the invention includes the proliferation of the differentiated cells and the formation of the cells into cardiac structures including coronary arteries, arterioles, capillaries, and myocardium. As one skilled in the art is aware, all of these structures are essential for proper function in the heart. It has been shown in the literature that implantation of cells including endothelial cells and smooth muscle cells will allow for the implanted cells to live within the infarcted region, however they do not form the necessary structures to enable the heart to regain full functionality.
  • the source of the tissue being grafted can be from other sources of tissue used in grafts of the heart.
  • compositions such as pharmaceutical compositions including somatic stem cells and/or at least one cytokine, for instance, for use in inventive methods for treating cardiovascular disease or conditions or cardiac conditions.
  • the cytokines in the pharmaceutical composition of the present invention may also include mediators known to be involved in the maintenance of early and late hematopoiesis such as IL-1 alpha and IL-1 beta, IL-6, IL-7, IL-8, IL-11 and IL-13; colony-stimulating factors, thrombopoietin, erythropoietin, stem cell factor, fit 3-ligand, hepatocyte cell growth factor or variants thereof, tumor necrosis factor alpha, leukemia inhibitory factor, transforming growth factors beta 1 and beta 3; and macrophage inflammatory protein 1 alpha), angiogenic factors (fibroblast growth factors 1 and 2, vascular endothelial growth factor) and mediators whose usual target (and source) is the connective tissue-forming cells (platelet-derived growth factor A, epidermal growth factor, transforming growth factors alpha and beta 2, oncostatin M and insulin-like growth factor-1), or neuronal cells (nerve growth factor) (Sensebe, L., et
  • the pharmaceutical composition of the present invention is delivered via injection.
  • routes for administration include, but are not limited to subcutaneous or parenteral including intravenous, intraarterial, intramuscular, intraperitoneal, intramyocardial, intracoronarial, transendocardial, trans-epicardial, intranasal administration as well as intrathecal, and infusion techniques.
  • the pharmaceutical composition is in a form that is suitable for injection.
  • a therapeutic of the present invention When administering a therapeutic of the present invention parenterally, it will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion).
  • the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Nonaqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions.
  • various additives which enhance the stability, sterility, and isotonicity of the compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.
  • Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various amounts of the other ingredients, as desired.
  • composition of the present invention e.g., comprising a therapeutic compound
  • any compatible carrier such as various vehicles, adjuvants, additives, and diluents
  • the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, iontophoretic, polymer matrices, liposomes, and microspheres.
  • the pharmaceutical composition utilized in the present invention can be administered orally to the patient.
  • Conventional methods such as administering the compounds in tablets, suspensions, solutions, emulsions, capsules, powders, syrups and the like are usable.
  • Known techniques which deliver the compound orally or intravenously and retain the biological activity are preferred.
  • a composition of the present invention can be administered initially, and thereafter maintained by further administration.
  • a composition of the invention can be administered in one type of composition and thereafter further administered in a different or the same type of composition.
  • a composition of the invention can be administered by intravenous injection to bring blood levels to a suitable level. The patient's levels are then maintained by an oral dosage form, although other forms of administration, dependent upon the patient's condition, can be used.
  • mice are treated generally longer than the mice or other experimental animals which treatment has a length proportional to the length of the disease process and drug effectiveness.
  • the doses may be single doses or multiple doses over a period of several days, but single doses are preferred.
  • animal experiments e.g., rats, mice, and the like, to humans, by techniques from this disclosure and documents cited herein and the knowledge in the art, without undue experimentation.
  • the treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient being treated.
  • the quantity of the pharmaceutical composition to be administered will vary for the patient being treated.
  • 2 ⁇ 10 4 ⁇ 1 ⁇ 10 5 stem cells and 50-500 ⁇ g/kg per day of a cytokine or variant of said cytokine are administered to the patient. While there would be an obvious size difference between the hearts of a mouse and a human, it is possible that 2 ⁇ 10 4 ⁇ 1 ⁇ 10 5 stem cells would be sufficient in a human as well.
  • the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including their size, age, size of the infarct, and amount of time since damage. Therefore, dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art.
  • any additives in addition to the active stem cell(s) and/or cytokine(s) are present in an amount of 0.001 to 50 wt % solution in phosphate buffered saline, and the active ingredient is present in the order of micrograms to milligrams, such as about 0.0001 to about 5 wt %, preferably about 0.0001 to about 1 wt %, most preferably about 0.0001 to about 0.05 wt % or about 0.001 to about 20 wt %, preferably about 0.01 to about 10 wt %, and most preferably about 0.05 to about 5 wt %.
  • any composition to be administered to an animal or human it is preferred to determine therefore: toxicity, such as by determining the lethal dose (LD) and LD 50 in a suitable animal model e.g., rodent such as mouse; and, the dosage of the composition(s), concentration of components therein and timing of administering the composition(s), which elicit a suitable response.
  • toxicity such as by determining the lethal dose (LD) and LD 50 in a suitable animal model e.g., rodent such as mouse
  • LD 50 lethal dose
  • LD 50 low-d dose
  • suitable animal model e.g., rodent such as mouse
  • the dosage of the composition(s), concentration of components therein and timing of administering the composition(s) which elicit a suitable response.
  • compositions comprising a therapeutic of the invention include liquid preparations for orifice, e.g., oral, nasal, anal, vaginal, peroral, intragastric, mucosal (e.g., perlingual, alveolar, gingival, olfactory or respiratory mucosa) etc., administration such as suspensions, syrups or elixirs; and, preparations for parenteral, subcutaneous, intradermal, intramuscular or intravenous administration (e.g., injectable administration), such as sterile suspensions or emulsions.
  • Such compositions may be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose or the like.
  • compositions can also be lyophilized.
  • the compositions can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts, such as “REMINGTON'S PHARMACEUTICAL SCIENCE”, 17th edition, 1985, incorporated herein by reference, may be consulted to prepare suitable preparations, without undue experimentation.
  • compositions of the invention are conveniently provided as liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions or viscous compositions which may be buffered to a selected pH. If digestive tract absorption is preferred, compositions of the invention can be in the “solid” form of pills, tablets, capsules, caplets and the like, including “solid” preparations which are time-released or which have a liquid filling, e.g., gelatin covered liquid, whereby the gelatin is dissolved in the stomach for delivery to the gut. If nasal or respiratory (mucosal) administration is desired, compositions may be in a form and dispensed by a squeeze spray dispenser, pump dispenser or aerosol dispenser. Aerosols are usually under pressure by means of a hydrocarbon. Pump dispensers can preferably dispense a metered dose or, a dose having a particular particle size.
  • compositions of the invention can contain pharmaceutically acceptable flavors and/or colors for rendering them more appealing, especially if they are administered orally.
  • the viscous compositions may be in the form of gels, lotions, ointments, creams and the like (e.g., for transdermal administration) and will typically contain a sufficient amount of a thickening agent so that the viscosity is from about 2500 to 6500 cps, although more viscous compositions, even up to 10,000 cps may be employed.
  • Viscous compositions have a viscosity preferably of 2500 to 5000 cps, since above that range they become more difficult to administer. However, above that range, the compositions can approach solid or gelatin forms which are then easily administered as a swallowed pill for oral ingestion.
  • Liquid preparations are normally easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, liquid compositions are somewhat more convenient to administer, especially by injection or orally. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with mucosa, such as the lining of the stomach or nasal mucosa.
  • suitable carriers and other additives will depend on the exact route of administration and the nature of the particular dosage form, e.g., liquid dosage form (e.g., whether the composition is to be formulated into a solution, a suspension, gel or another liquid form), or solid dosage form (e.g., whether the composition is to be formulated into a pill, tablet, capsule, caplet, time release form or liquid-filled form).
  • liquid dosage form e.g., whether the composition is to be formulated into a solution, a suspension, gel or another liquid form
  • solid dosage form e.g., whether the composition is to be formulated into a pill, tablet, capsule, caplet, time release form or liquid-filled form.
  • Solutions, suspensions and gels normally contain a major amount of water (preferably purified water) in addition to the active compound. Minor amounts of other ingredients such as pH adjusters (e.g., a base such as NaOH), emulsifiers or dispersing agents, buffering agents, preservatives, wetting agents, jelling agents, (e.g., methylcellulose), colors and/or flavors may also be present.
  • pH adjusters e.g., a base such as NaOH
  • emulsifiers or dispersing agents e.g., a base such as NaOH
  • buffering agents e.g., preservatives
  • wetting agents e.g., methylcellulose
  • jelling agents e.g., methylcellulose
  • colors and/or flavors e.g., methylcellulose
  • compositions of this invention may be accomplished using sodium chloride, or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solutes.
  • sodium chloride is preferred particularly for buffers containing sodium ions.
  • Viscosity of the compositions may be maintained at the selected level using a pharmaceutically acceptable thickening agent.
  • Methylcellulose is preferred because it is readily and economically available and is easy to work with.
  • suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of the thickener will depend upon the agent selected. The important point is to use an amount which will achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents.
  • a pharmaceutically acceptable preservative can be employed to increase the shelf-life of the compositions.
  • Benzyl alcohol may be suitable, although a variety of preservatives including, for example, parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed.
  • a suitable concentration of the preservative will be from 0.02% to 2% based on the total weight although there may be appreciable variation depending upon the agent selected.
  • compositions should be selected to be chemically inert with respect to the active compound. This will present no problem to those skilled in chemical and pharmaceutical principles, or problems can be readily avoided by reference to standard texts or by simple experiments (not involving undue experimentation), from this disclosure and the documents cited herein.
  • compositions of this invention are prepared by mixing the ingredients following generally accepted procedures.
  • the selected components may be simply mixed in a blender, or other standard device to produce a concentrated mixture which may then be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a buffer to control pH or an additional solute to control tonicity.
  • the pH may be from about 3 to 7.5.
  • Compositions can be administered in dosages and by techniques well known to those skilled in the medical and veterinary arts taking into consideration such factors as the age, sex, weight, and condition of the particular patient, and the composition form used for administration (e.g., solid vs. liquid). Dosages for humans or other mammals can be determined without undue experimentation by the skilled artisan, from this disclosure, the documents cited herein, and the knowledge in the art.
  • Suitable regimes for initial administration and further doses or for sequential administrations also are variable, may include an initial administration followed by subsequent administrations; but nonetheless, may be ascertained by the skilled artisan, from this disclosure, the documents cited herein, and the knowledge in the art.
  • compositions of the present invention are used to treat cardiovascular diseases, including, but not limited to, atherosclerosis, ischemia, hypertension, restenosis, angina pectoris, rheumatic heart disease, congenital cardiovascular defects and arterial inflammation and other diseases of the arteries, arterioles and capillaries or related complaint.
  • cardiovascular diseases including, but not limited to, atherosclerosis, ischemia, hypertension, restenosis, angina pectoris, rheumatic heart disease, congenital cardiovascular defects and arterial inflammation and other diseases of the arteries, arterioles and capillaries or related complaint.
  • the invention involves the administration of stem cells as herein discussed, alone or in combination with one or more cytokine or variant of said cytokine, as herein discussed, for the treatment or prevention of any one or more of these conditions or other conditions involving weakness in the heart, as well as compositions for such treatment or prevention, use of stem cells as herein discussed, alone or in combination with one or more cytokine or variant thereof, as herein discussed, for formulating such compositions, and kits involving stem cells as herein discussed, alone or in combination with one or more cytokine or cytokine variant, as herein discussed, for preparing such compositions and/or for such treatment, or prevention.
  • advantageous routes of administration involves those best suited for treating these conditions, such as via injection, including, but are not limited to subcutaneous or parenteral including intravenous, intraarterial, intramuscular, intraperitoneal, intramyocardial, intracoronarial, transendocardial, trans-epicardial, intranasal administration as well as intrathecal, and infusion techniques.
  • subcutaneous or parenteral including intravenous, intraarterial, intramuscular, intraperitoneal, intramyocardial, intracoronarial, transendocardial, trans-epicardial, intranasal administration as well as intrathecal, and infusion techniques.
  • Myocardial tissue (averaging 1 g or less in weight) was harvested from consenting patients who underwent cardiac surgery under sterile conditions in the operating room. Samples were minced and seeded onto the surface of uncoated Petri dishes containing a medium supplemented with hepatocyte growth factor and insulin-like growth factor-1 at concentrations of 200 ng/ml. Cells outgrown from the tissue were sorted for c-kit with immunobeads and cultured (Beltrami, 2003; Linke, 2005). Cell phenotype was defined by FACS and immunocytochemistry as described previously (Beltrami, 2003; Orlic, 2001; Urbanek, 2005).
  • the human c-kit positive cells (human cardiac stem cells, hCSCs) were plated in 35 mm diameter culture dishes at the same density and cultured under standard conditions in F12 medium with 10% fetal bovine serum (FBS) for at least 48 hours to support cell attachment and settling. At 70-80% confluence, medium was changed and a two-step starvation was performed, reducing the initial FBS concentration to 5% and, after 24 hours to 0.5%.
  • FBS fetal bovine serum
  • HGF hepatocyte growth factor
  • HP21, HP11, NK1, or 1K1 hepatocyte growth factor
  • BrdU 1 ⁇ g/ml was added three times every twelve hours. After 24 hours of incubation, culture dishes were fixed in ethanol fixative and proliferation was detected and measured via BrdU labeling (Roche Applied Science). The percentage of BrdU labeled cells for each condition is shown in Table 1 below.
  • the amino acid numbers in the mutation designations refer to the amino acid positions in the wild-type HGF protein (SEQ ID NO: 1). Note that the HGF used in this Example and the following examples did not contain the first 31 amino acids (leader sequence) of SEQ ID NO: 1 as these amino acids are cleaved upon secretion of the peptide from the cells, so that the active molecule does not posses this leader sequence.
  • NK1 is a natural splice variant of HGF and contains amino acids 32-206 of the wild-type HGF protein.
  • SEQ ID NO: 4 includes an additional four amino acids at the N- and C-terminus for experimental convenience.
  • 1K1 is a mutant of NK1 and contains amino acid substitutions as designated at positions 132 and 134. The results of this experiment show that all of the HGF variants could induce proliferation of hCSCs approximately 2 fold over controls. The HP11 variant appeared to induce the greatest amount of proliferation.
  • Human cardiac stem cells (c-kit positive cells) were plated in 35 mm diameter culture dishes at the same density and cultured under standard conditions in F12 medium with 10% FBS for at least 48 hours to support cell attachment and settling.
  • medium was changed and HGF or a variant of HGF (HP21, HP11, NK1, or 1K1) was added at a molar concentration of 100 ng/ml, corresponding to 1,245 ⁇ 10 ⁇ 15 M to each culture dish and kept in an incubator, under sterile conditions (37° C., 5% CO 2 atmosphere). None was added to control cultures.
  • xanthine 0.5 mM
  • xanthine oxidase 100 mU/ml
  • culture dishes 24 hours after addition of the apoptotic stimuli, culture dishes were fixed in 4% methanol-free formaldehyde in HBSS for 20 minutes in ice and stored for one hour in 70% ethanol at ⁇ 20° C.
  • Apoptosis was detected and measured via TdT labelling (Apoalert DNA Fragmentation Kit, Clontech). The results of the apoptosis assay are depicted in Table 2.
  • variants of HGF in particular the full-length variants (HP21 and HP11) drastically reduce the number of hCSCs that undergo apoptosis in response to an inducing stimulus.
  • NK1 and Other HGF Variants Mobilize Human Cardiac Stem Cells to Sites of Injury
  • This experiment was to examine the ability of NK1 and other HGF variants to induce migration of hCSCs to injured tissue in an in vitro wound healing assay.
  • This in vitro methodology consists of the disruption of the confluent layer of cells in the culture dish. Subsequently, the ability of the tested cells to migrate towards the disrupted area is measured in terms of number of cells and speed of locomotion. Both the speed of stem cell migration towards the wound and the number of stem cells found in the wound area were calculated. The results are shown in Tables 3 and 4.
  • HGF/SF HGF/SF NK1 R73E R73E:R76 NK1 K132E:K134E ctrl HGF/SF HP21 (HP11) (NK1) (1K1) # of cells migrating towards wound May 23, 2007 set #1 DHT 0083 p5 7 24 26 20 22 13 May 23, 2007 set #2 DHT 0083 p5 10 26 30 36 25 14 May 25, 2007 set #1 DHT 0083 p7 14 40 45 24 21 36 May 25, 2007 set #2 DHT 0083 p7 36 58 63 38 35 23 May 25, 2007 set #3 DHT 0083 p7 38 61 44 29 45 42 May 25, 2007 set #4 DHT 0083 p7 27 36 48 59 51 35 Jun.
  • HGF variants can affect both the migration rate and number of migrating stem cells. All of the proteins produced at least a 1.4 fold increase in migration rate of the stem cells over controls. HP21 had the greatest influence on stem cell migration rate, while 1K1 had the least effect. Table 4 shows that HGF and its variants had a corresponding effect on the number of stem cells found in the wound area. Wild-type HGF had the most significant effect. However, the variants produced notable increases in the number of stem cells found in the wound compared to controls.
  • clonogenic EGFP POS -c-kit POS -CSCs were injected intramyocardially subsequent to the induction of myocardial infarction by coronary artery occlusion. Subsequently, four injections of IGF-1 and either HP11, HGF, or NK1 were made from the AV-groove to the border zone of the infarct. The concentration of IGF-1 was 200 ng/ml at each of the four sites of injection.
  • HP11, HGF, or NK1 was injected at increasing concentrations, from the atria to the border zone: 50 ng/ml (AV groove), 100 ng/ml (mid-region) and 200 ng/ml (two opposite sides of the infarct border zone).
  • hCSCs were injected at opposite sites of the border zone and co-injected with rhodamine-labeled microspheres to mark the injection sites.
  • the migration rate was monitored ex vivo by two photon microscopy.
  • the calculated migration rates for the implanted hCSCs that were subsequently mobilized with injections of either HGF and IGF-1 or HP11 and IGF-1 are shown in Table 5.
  • a chemotactic gradient of NK1 was created by injecting increasing concentrations of NK1 from the atria to the border zone as follows: 50 ng/ml (AV groove), 100 ng/ml (mid-region), and 200 ng/ml (two opposite sides of the infarct border zone).
  • mice were sacrificed and the myocardium was fixed in 10% formalin.
  • Tissues were processed for staining and identification of newly formed myocytes. Newly formed myocytes were labeled with antibodies to ⁇ -sacromeric actin. The results of these experiments are shown in FIGS. 2A and B.
  • the figure shows that the mid-portion (panel A) and the subendocardial region (panel B) of the infarct were replaced by a band of regenerated myocytes as indicated by the bright red fluorescence corresponding to ⁇ -sacromeric actin.
  • the blue label in the figure shows nuclei stained by DAPI.
  • NK1 and 1K1 like HGF are capable of mobilizing resident cardiac stem cells to the site of injured tissue where they differentiate into new myocytes to effect structural and functional repair of the infarcted tissue.

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